High pancuronium sensitivity of axonal nicotinic‐acetylcholine receptors in humans during organophosphate intoxication

Abstract

The effect of low-dose pancuronium on neuromuscular transmission was studied in 2 patients during the early and late stages of severe organophosphate intoxication. Single evoked compound muscle action potentials (CMAP) were followed by repetitive discharges and a decrement-increment (D-I) phenomenon with 10-, 20-, and 50-Hz supramaximal nerve stimulation. Intravenous pancuronium, 1 mg, abolished the D-I phenomenon, while the repetitive discharges of the CMAP were only partially reduced. It is postulated, that the disappearance of the D-I phenomenon with persistence of the CMAP repetitive discharges results from blockade of nicotinic-acetylcholine receptors located on the terminal axon responsible for stimulus-induced antidromic backfiring. This response to a very low dose of pancuronium indicates a high sensitivity of the axonal nicotinic-acetylcholine receptor to pancuronium in humans, as had been previously postulated from animal experiments.

Organophosphorus poisoning and anaesthesia

“…There is a rapid onset of difficulty in breathing associated with the use of the accessory muscles of respiration and, if untreated, death follows rapidly as a result of ventilatory [23,62]. The decrement response seen initially during the intermediate syndrome is similar to TOF fade and tetanic fade, which is usually attributed to a decrease in the effectiveness of the presynaptic cholinergic feedback mechanism and is associated with partial or recovering nondepolarising block.…”

“…The repetitive firing following a single evoked compound muscle action potentials is considered to be due to excessive acetylcholine in the presence of an anticholinesterase, causing antidromic firing due to stimulation of the axonal (presynaptic) nicotinic receptors [66]. Besser et al [23] showed that pancuronium 1 mg, which acts both pre-and postsynaptically, abolished the D-I phenomenon and partially reduced the repetitive discharge of the compound muscle action potentials in two patients with OP poisoning [23].…”

“…Organophosphorusbased pesticides are widely used globally and have emerged as the major pesticide contributor to ill health [2]. Ill health related to these irreversible inhibitors of acetylcholinesterase has been reported recently in studies from China [3], India [4][5][6], Brazil [7], Mexico [8], Canada [9], Costa Rica [10], Columbia [11], Puerto Rico [12], France [13], Spain [14,15], Poland [16], Italy [17,18], Belgium [19], Romania [20], Portugal [21], Greece [22], Germany [23], Japan [24], Jordan [25], South Africa [26], Turkey [27], Taiwan [28] and Sri Lanka [29,30]. In 1996, the American Association of Poison Control Centers reported 86 914 human exposures to pesticides in the US [31].…”

Prolonged Administration of Pyridostigmine Impairs Neuromuscular Function with and without Down-regulation of Acetylcholine Receptors

“…43,44 Consistently, patients exposed to organophosphate poisoning are more sensitive than resistant to pancuronium. 45 The increased sensitivity to atracurium in our studies reflects the decreased margin of safety of neurotransmission induced by pyridostigmine, either due to its direct allosteric interaction with the acetylcholine receptors, or due to desensitization of acetylcholine receptors by acetylcholine. 17 Our observation that the dose-response curves of atracurium can indeed shift to the left is in agreement with the clinical scenario, where chronic cholinesterase inhibition induced by organophosphate poisoning made patients more sensitive to nondepolarizers.…”

Clinical Toxicology of Anticholinesterase Agents in Humans

“…Decremental response to repetitive nerve stimulation dramatically worsened after injection of edrophonium (Maselli et al, 1986), indicating the effects of a further excess of acetylcholine, whereas the administration of pancuronium improved neuromuscular transmission, indicating a blockade of nicotinic receptors (Besser et al, 1990(Besser et al, , 1991. Distinction between these findings and those detected during the intermediate syndrome may be difficult (see Section 72.2.3.2).…”